Chemical process for the preparation of intermediates to obtain n-formyl hydroxylamine compounds

ABSTRACT

Improved processes for preparing intermediates useful for preparing antibacterial N-[1-oxo2-alkyl-3-(N-hydroxyformamido)-propyl}-(carbonylamino-aryl or -heteroaryl)-azacyclo4-7alkanes or thiazacyclo4-7alkanes, which have one or more of the following features: (1) make use of a particular I3-lactam intermediate; (2) which make use of a particular resolving agents, enantiomerically pure substituted propionic acids, especially (R)-2-butyl-3-hydroxypropionic acid; (3) which avoid the use of hydrogen peroxide; and (4) which facilitate selective debenzylation reducing production of waste by-products.

FIELD OF INVENTION

This invention is directed to a process for preparing certainantibacterial N-formyl hydroxylamine compounds.

BACKGROUND OF THE INVENTION

PDF is a metallopeptidase found in prokaryotic organisms, such asbacteria. Protein synthesis in prokaryotic organisms begins withN-formyl methionine (fMet). After initiation of protein synthesis, theformyl group is removed by the enzyme PDF; this activity is essentialfor maturation of proteins. It has been shown that PDF is required forbacterial growth. See Chang et al., J. Bacteriol., Vol. 171, pp.4071-4072 (1989); Meinnel et al., J. Bacteriol., Vol. 176, No. 23, pp.7387-7390 (1994); and Mazel et al., EMBO J., Vol. 13, No. 4, pp. 914-923(1994). Since protein synthesis in eukaryotic organisms does not dependon fMet for initiation, agents that will inhibit PDF are attractivecandidates for development of new anti-microbial and anti-bacterialdrugs.

Co-pending application Ser. No. 10/171,706, filed Jun. 14, 2002(incorporated herein by reference in its entirety), PCT equivalentpublished as WO 02/102790 A1, discloses novel N-formyl hydroxylaminecompounds that inhibit PDF and are therefore useful as antibacterialagents. The compounds disclosed therein are certainN-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl}-(carbonylamino-aryl or-heteroaryl)-azacyclo4-7alkanes or thiazacyclo4-7alkanes, which aredescribed in more detail hereinafter. Additionally, PCT application WO99/39704 discloses other N-formyl hydroxylamine derivatives that areantibacterial agents by virtue of their PDF inhibiting capabilities.Improved processes have been discovered for preparing intermediatesuseful for preparing theseN-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl](carbonylamino-aryl or-heteroaryl)-azacyclo4-7alkanes or thiazacyclo4-7alkanes, which have oneor more of the following features: (1) make use of a particular β-lactamintermediate; (2) which make use of particular resolving agents, e.g.,enantiomerically pure substituted propionic acids, especially(R)-2-butyl-3-hydroxy-propionic acid; (3) which avoid the use ofhydrogen peroxide (the use of hydrogen peroxide can be a safety concernbecause of its instability, therefore, this aspect of the invention issafer than the prior art process); and (4) which facilitate selectivedebenzylation, reducing production of waste by-products.

SUMMARY OF THE INVENTION

The present invention is directed to the novel processes for preparingcertain intermediates which are useful to prepare certain N-formylhydroxylamine compounds which are useful for inhibiting bacteria.

More specifically, the present invention is directed to a process forpreparing a compound of formula (IX)

comprising Step A:

Contacting a compound of formula (I)

with a compound of the formula (II)

Y—O—NH₂  (II)

in a suitable solvent under conditions suitable to form a compound ofthe formula (III)

followed by asymmetric hydrogenation Step B:

Contacting the compound of formula (III) with hydrogen in the presenceof a chiral ligand and a catalytic amount of a hydrogenation catalyst ina suitable solvent and under conditions suitable to form a compound ofthe formula (IV)

followed by Step C:

Contacting the compound of formula (IV) with a base such as a Grignardreagent in a suitable solvent under conditions suitable to form acompound of the formula (V)

followed by Step D:

Contacting the compound of formula (V) with a compound of the formula(VI)

in a suitable solvent, optionally in the presence of an activator underconditions suitable to form a compound of the formula (VII)

followed by Step E:

Contacting the compound of formula (VII) with a formylating agent in asuitable solvent under conditions suitable to form the compound offormula (VIII):

followed by Step F:

Converting the compound of formula (VIII) to the compound of formula(IX) by removing the hydroxy-protecting group using conventionalhydrogenation techniques known in the art, e.g., by contacting thecompound of formula (VIII) with hydrogen in the presence of a palladiumcatalyst, such as Pd/BaSO4, to form the compound of formula (IX)

wherein

-   -   X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF₂—,        —C═N(OR)— or —CH(F)—;    -   Y is a hydroxyl-protecting group such as benzyl;    -   R is alkyl;    -   Ac is acetyl;    -   each of R₂, R₃, R₄, R₅, and R₁₀ and independently is hydrogen or        alkyl, or (R₂ or R₃) collectively form a C₄-C₇cycloalkyl    -   R′ is alkyl or aryl; and    -   n is 0-3, provided that when n is 0, X is —CH₂—.

Furthermore, the present invention discloses process for preparing acompound of formula (IX) making use of enantiomerically pure substitutedpropionic acids, especially (R)-2-butyl-3-hydroxy-propionic acid

More specifically, the present invention is directed to a process forpreparing a compound of the formula (X)

comprising Step 1:

Resolution of a racemate of the compound of the formula (X), i.e., acompound of formula (XI):

by contacting the compound of formula (XI) with (R)-α-methylbenzylaminein a suitable solvent to form a (R,R)-diasteromeric salt of formula(XII)

followed by Step 2:

Contacting the compound of formula (XII) with a biphasic mixture of anaqueous mineral acid and an organic solvent to form the compound offormula (XI),

wherein

-   -   each of R₂, R₃, R₄ and R₅ is, independently, hydrogen or alkyl;        or R₂ and R₃, collectively, form a C₄-C₇cycloalkyl, provided        that R₄ and R₅ are different.

In addition, the present invention discloses process for preparing acompound of formula (IX) making use of a two-step process for preparinga compound of formula (XIII)

comprising Step i:

Contacting a compound of the formula (XIV)

with an alkoxide of p-methoxybenzyl alcohol, in a suitable solvent underconditions to form a compound of formula (XV)

followed by deprotection Step ii:

Contacting the compound of formula (XV) with a strong organic acid in asuitable solvent under conditions to form the compound of formula(XIII),

wherein

R₄ is alkyl;

Bn is benzyl; and

Me is methyl.

The present invention also provides a process for selectively convertingthe compound of formula (VIII) to the compound of formula (IX) byremoving the hydroxy-protecting group, preferably benzyl, by contactingthe compound of formula (VIII) with molecular hydrogen atsub-atmospheric pressures in the presence of a palladium catalyst inethanol to form the compound of formula (IX).

Another aspect of the present invention is directed to a process forconverting the compound of formula (XXV) to a compound of formula (XXVI)by removing hydroxyl-protecting group, preferably benzyl, by contactingthe compound of formula (XXV) with a hydrogen transfer reagentcomprising 4-methylmorpholine and formic acid in the presence of apalladium catalyst.

In addition to the above processes comprising multiple steps, e.g. StepsA-F, Steps 1-8, Steps i-ii, the present invention is directed to each ofthe steps individually, and to any two or more sequential steps.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention provides a process for preparingintermediates useful in the preparation of aN-[1-oxo-2-alkyl-3-(N-hydroxyformamido)propyl]-(carbonylamino-aryl or-heteroaryl)-azacyclo₄₋₇alkanes or thiazacyclo₄₋₇alkanes, e.g., acompound of formula (IX)

wherein R₁, R₂, R₃, R₄, R₄, X and n are as defined above.

To convert the compound of formula (VIII) to the compound of formula(IX). Step F can be performed wherein the hydroxyl-protecting group isremoved using conventional hydrogenation techniques known in the art,e.g., by contacting the compound of formula (VIII) with hydrogen in thepresence of a palladium catalyst, such as Pd/BaSO₄.

Preferred compounds discussed herein, e.g., of formula (IX), aredisclosed in U.S. Ser. No. 10/171,706. For example, in the compoundsdescribed above, especially the compound of formula (IX), the followingsignificances are preferred individually or in any sub-combination:

1. R₁ is a heteroaryl of formula (II.1)

wherein

R₆, R₇ and R₉ are hydrogen; and

R₈ is methyl or trifluoromethyl; or

R₆, R₇ and R₈ are hydrogen; and

R₉ is fluoro; or

R₆, R₈ and R₉ are hydrogen; and

R₇ is ethyl or methoxy; or

R₇, R₈ and R₉ are hydrogen; and

R₆ is hydroxy; or

R₇ and R₈ are hydrogen;

R₆ is methoxy; and

R₉ is methyl; or

R₁ is a heteroaryl of formula (III.1)

wherein

-   -   R₆, R₇ and R₉ are hydrogen; and    -   R₈ is fluoro or trifluoromethyl; or    -   R₆, R₈ and R₉ are hydrogen; and    -   R₇ is ethyl;        -   preferably R₁ is a heteroaryl of formula (II.1),        -   wherein            -   R₆, R₈ and R₉ are hydrogen; and            -   R₇ is ethyl        -   or R₁ is a heteroaryl of formula (III.1),            -   wherein                -   R₅, R₇ and R₉ are hydrogen; and                -   R₈ is fluoro.                    2. X is —CH₂—, —CH(OH)—, —CH(OR)—, —CF₂— or —CH(F)—,                    preferably X is —CH₂—;                    3. R₂, R₃, R₅ are hydrogen;                    4. R₄ and R₁₀ are alkyl, preferably C₁-C₆ alkyl for                    R₄, such as n-butyl, and C₁-C₅ alkyl for R₁₀ such as                    n-propyl;                    5. n is 1.

Unless otherwise stated, the following terms as used in thespecification have the following meaning.

The term “alkyl” refers to saturated aliphatic groups, includingcycloalkyl or substituted alkyl, preferably straight-chain,branched-chain and cyclic groups having from 1-10 carbons atoms. Morepreferably, “alkyl” or “alk”, whenever it occurs, is a C₁-C₇alkyl,particularly, C₁₋₄alkyl. Examples of “alkyl” or “alk” include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl,cyclopropyl and especially n-butyl.

The term “cycloalkane” or “cycloalkyl” contains from 3- to 7-ring carbonatoms, and is, e.g., cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term “aryl” or “Ar” refers to an aromatic carbocyclic group of 6-14carbon atoms having a single ring including, but not limited to, groups,such as phenyl; or multiple condensed rings including, but not limitedto, groups, such as naphthyl or anthryl; and, is especially, phenyl.

The term “heteroaryl” or “HetAr” refers to a 4- to 7-membered,monocyclic aromatic heterocycle or a bicycle that is composed of a 4- to7-membered, monocyclic aromatic heterocycle and a fused-on benzene ring.The heteroaryl has at least one hetero atom, preferably one or twoheteroatoms including, but not limited to, heteroatoms, such as N, O andS, within the ring. A preferred heteroaryl group is pyridinyl,pyrimidinyl or benzdioxolanyl.

The aryl or heteroaryl may be substituted or unsubstituted by one ormore substituents including, but not limited to, C₁-C₇alkyl,particularly, C₁-C₄alkyl, such as methyl, hydroxy, alkoxy, acyl,acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl,heteroalkylaryl, alkylsulfonyl and formyl.

The term “heteroalkyl” refers to saturated or unsaturated C₁-C₁₀alkyl asdefined above and, especially, C₁-C₄heteroalkyl which contain one ormore heteroatoms, as part of the main, branched or cyclic chains in thegroup. Heteroatoms may independently be selected from the groupconsisting of —NR—, where R is hydrogen or alkyl, —S—, —O— and —P—;preferably —NR—, where R is hydrogen or alkyl; and/or —O—. Heteroalkylgroups may be attached to the remainder of the molecule either at aheteroatom (if a valence is available) or at a carbon atom. Examples ofheteroalkyl groups include, but are not limited to, groups, such as—O—CH₃, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —S—CH₂—CH₂—CH₃, —CH₂—CH(CH₃)—S—CH₃and —CH₂—CH₂—NH—CH₂—CH₂—

The term “alkoxy”, as used herein, refers to a C₁-C₁₀alkyl linked to anoxygen atom, or preferably, C₁-C₇alkoxy, more preferably, C₁-C₄alkoxy.Examples of alkoxy groups include, but are not limited to, groups suchas methoxy, ethoxy, n-butoxy, tert-butoxy and allyloxy.

The term “acyl”, as used herein, refers to the group —(O)CR, where R isalkyl, especially, C₁-C₇alkyl, such as methyl. Examples of acyl groupsinclude, but are not limited to, acetyl, propanoyl and butanoyl.

The term “acyloxy”, as used herein, refers to the group —OC(O)R, whereinR is hydrogen, alkyl, especially, C₁-C₇alkyl, such as methyl or ethyl,or phenyl or substituted alkyl as defined above.

The term “alkoxycarbonyl”, as used herein, refers to the group —COOR,wherein R is alkyl, especially, C₁-C₇alkyl, such as methyl or ethyl.

The term “halogen” or “halo” as used herein, refers to chlorine,bromine, fluorine, iodine and, is especially, fluorine.

The term “thioalkoxy”, as used herein, means a group —SR, where R is analkyl as defined above, e.g., methylthio, ethylthio, propylthio,butylthio and the like.

The term “heteroalkylaryl”, as used herein, means a heteroalkyl group,e.g., —O—CH₂-substituted with an aryl group, especially, phenyl. Thephenyl group itself may also be substituted with one or moresubstituents, such as halogen, especially fluoro and chloro; and alkoxy,such as methoxy.

The term “alkylsulfonyl”, as used herein, means a group —SO₂R, wherein Ris alkyl, especially, C₁-C₇alkyl, such as methyl sulfonyl.

The term “enantiomericly pure” or “optically pure” means that theenantiomeric purity is greater than 55%, preferably greater than 80%,more preferably greater than 90%, and most preferably greater than 95%.

To prepare the compounds of formula (I), a compound of the formula

is contacted with a compound of the formula

in the presence of a catalytic amount of a catalyst, such as DABCO, DBUor DBN under sufficient conditions to form a compound of the formula

The above reaction is a Baylis-Hillman reaction.

The compound thus formed can then be reacted with acetic anhydride in asuitable solvent, in the presence of a base, such as 4-DMAP or atrialkylamine, e.g., triethylamine or tripropylamine, to form thecompound of formula (I).

Preferably R₂ and R₃ are hydrogen and R₄ is n-propyl; which results in acompound such as formula (Ic)

The solvent used for the various steps A-F are typically organicsolvents, although in some situations, aqueous/organic solvents can beused. Examples of suitable solvents include dioxane, methylene chloride,dichloromethane, toluene, acetone, methylethylketone, THF, isopropylacetate, DMF, alcohols, especially higher-branched alcohols, such ast-butanol and the like.

For Step A, a typical temperature is about 10° C. to about 50° C.,preferably about 20° C. to about 25° C. The solvent for Step A istypically THF, DMF, NMP and the like.

For asymmetric hydrogenation Step B, a typical temperature is about 10°C. to about 50° C., preferably about 20° C. to about 25° C. The solventfor Step B is not known to be critical and can be a wide variety ofsolvents, such as dioxane, methylene chloride, dichloromethane, toluene,acetone, methylethylketone, THF, isopropyl acetate, DMF, alcohols,especially higher-branched alcohols, such as t-butanol and the like. Thehydrogen for Step is typically in the form of hydrogen gas and the StepB is typically preformed above atmospheric pressure, e.g., at about 40psi to about 100 psi, more typically at about 45 psi to about 55 psi.The chiral ligand for Step B can be (2S,5S)-Me-Duphos,(1R,1′R,2S,2′S)-TangPhos and the like. (1R,1′R,2S,2′S)-TangPhos has theformula

The amount of Chiral ligand is typically about 1 mole % to about 15 mole% relative to the substrate. The hydrogenation catalyst is preferablyhomogenous. The hydrogenation catalyst is preferably a transition metalcomplex. Typical transition metal catalysts contain rhodium (Rh I) orruthenium (Ru II). A preferred catalyst is bis(norbornadiene)rhodium(I)tetrafluoroborate. The amount of catalyst is a catalytic amount,typically about 1 mole % to about 5 mole % relative to the substrate.

For cyclization Step C, a typical temperature is about −10° C. to about20° C., preferably about 0° C. The pH for Step C is basic, typically,about 8 pH to about 12 pH. The Grignard reagent used in Step C can beany suitable organomagnesium compound known in the art, such asmethylmagnesium chloride, ethylmagnesium chloride, isopropyl magnesiumchloride, n-butylmagnesium chloride, methylmagnesium bromide,isopropylmagnesium bromide, cyclopropylmagnesium bromide, ethylmagnesiumiodide and the like. The amount of Grignard reagent employed is ade-protonating amount which is typically in molar excess to the amountof formula (IV), e.g., about 1-5 equivalents relative to formula (IV). Apreferred solvent is acetone or methylethylketone.

For Step D, a typical temperature is about 30° C. to about 150° C.,preferably about 60° C. to about 80° C. The pH for Step D is typicallyabout 5 pH to about 11 pH. The activator for Step D is a compound whichprotonates the β-lactam keto oxygen; such activators include, e.g., mild(weak) organic acids, such as branched or unbranched carboxylic acids,e.g., 2-ethylhexanoic acid, acetic acid, isobutryic acid and the like.If an aqueous alcoholic solvent is used an activator is not needed;preferred aqueous alcoholic solvents include MeOH.H₂O, EtOH.H₂O and thelike. If an activator is used a preferred solvent is THF, dioxane ordimethoxyethane. If an activator is used it is used in an protonatingamount which is typically about 0.1 molar equivalents to about 2 molarequivalents relative to formula (V).

For Step E, a typical temperature is about −30° C. to about 50° C.,preferably about 0° C. to about 25° C. The pH for Step E is not criticaland can vary considerably. For Step E the solvent should not be analcoholic solvent. The formylating agent can be, e.g., HCO₂H/Ac₂O,trifluoroethylformate and the like, and is present in a formylatingamount which is typically about 1 molar equivalent to about 2 molarequivalents relative to formula (VII). A preferred solvent is EtOAc,isopropylacetate, t-butylacetate or THF.

To prepared the S enantiomer instead of the R enantiomer of thecompounds prepared herein, the appropriate isomer of the chiral ligandwill be used, e.g., (2R,5R)-Me-Duphos and (1S,1′S,2R,2′R)-TangPhos. Forexample, Step B will comprise:

Contacting a compound of the formula (III)

with hydrogen in the presence of a chiral ligand and a catalytic amountof a hydrogenation catalyst in a suitable solvent and under conditionssuitable to form a compound of the formula (IV′)

All of the other steps will be the same.

Insofar as the production of starting materials is not particularlydescribed, the compounds are known or may be prepared analogously tomethods known in the art or as disclosed in the examples hereinafter.

It is further preferred that in the optically pure compound of formula(X) that R₂, R₃ and R₅ are hydrogen and that R₄ is alkyl; such acompound has the formula (Xa)

Preferably in formula (X), R₄ is n-butyl, where such compound has theformula (Xb)

It is even more preferred that R₂, R₃ and R₅ are hydrogen and that R₄ isn-butyl where such compound has the structure (Xc):

To prepare the starting material of the above-described process, i.e.,formula (XI), the corresponding alkyl ester can be hydrolyzed asdescribed by Stetter and Kuhlmann, Synthesis, pp. 29-30 (1979).

For example, in a preferred preparation, a compound of formula (XVII)

is contacted with a strong base, such as KOH, to form a compound offormula (XVIII)

followed by contacting the compound of formula (XVIIII) with a reducingagent, such as LiBH₄, NaBH₄ or borane in a suitable solvent, such asTHF, DMF or diethyl ether, to form a starting material for the presentprocess, e.g., a compound of formula (IXa)

Following the first step (Step 1), it is preferred to re-crystallize thediasteriomeric salt from a suitable solvent, preferably from the samesolvent system, prior to performing the second step (step 2).

A preferred process of the invention comprises resolution of a compoundof formula (IXa) by contacting said compound with(R)-α-methylbenzylamine in a mixture of ethyl acetate and 2-propanol toform a compound of formula (IIIa)

followed by re-crystallization of the diasteriomeric salt, i.e., thecompound of formula (IIIa), from the same solvent, followed bycontacting the compound of formula (XIIa) with a mixture of HCl(preferably about 2 N), and isopropyl acetate to form the compound offormula (Xc)

To form the active antibacterial agents, a third step (Step 3) isperformed wherein the compound formed by the second step, i.e., thecompound of formula (X), is contacted with a compound of the formula(XIX)

Y—O—NH₂  (XIX)

in the presence of a carboxy-activating agent, in a suitable solventunder conditions suitable to form a compound of the formula (XX)

followed by Step 4:

Contacting a formula (XX) with a compound of the formula (XXI)

R′—SO₂—X′  (XXI)

wherein R′ is alkyl or aryl and X′ is halo, in the presence of a base ina suitable solvent, under conditions suitable to form a compound of theformula (XXII)

followed by Step 5:

Contacting a formula (XXII) with a base in a suitable solvent underconditions suitable to form a compound of the formula (XXIII)

followed by Step 6:

Contacting a formula (XXIII) with a compound of the formula (VI)

in a suitable solvent optionally in the presence of an activator underconditions suitable to form a compound of the formula (XXIV)

followed by Step 7:

Contacting a formula (XXIV) with a formylating agent in a suitablesolvent under conditions suitable to form compound (XXV):

followed by Step 8:converting the compound of formula (XXIV) to the compound of formula(IX) by removing the hydroxy-protecting group using conventionalhydrogenation techniques known in the art, e.g., by contacting thecompound of formula (XXIV) with hydrogen in the presence of a palladiumcatalyst, such as Pd/BaSO₄, to form the compound of formula (IX)

If desired, the (S) enantiomer can be prepared instead of the (R)enantiomer by using the (S) form of the resolving agent rather than the(R) form. Such a process comprises preparing a compound of the formula(X′)

comprising Step 1′:

Resolution a racemate of the compound of the formula (X′), i.e., acompound of formula (XI):

by contacting the compound of formula (X′) with (S)-α-methylbenzylaminein a suitable solvent to form a (S,S)-diasteromeric salt of formula(III′)

followed by Step 2′:

Contacting the compound of formula (XII′) with a biphasic mixture of anaqueous mineral acid and an organic solvent to form the compound offormula (X′). The active (S) antibacterial agents can then be preparedusing Steps 3-8 as described above.

Pressure is not known to be critical for carrying out the various steps1-8 and 1′-2′ of the invention. Generally, depending on the particularstep, a temperature of about −10° C. to about 150° C., preferably about0° C. to about 80° C., is typically employed. Typically aboutatmospheric pressure is used for convenience; however, variations toatmospheric pressure are not known to be detrimental. Oxygen is notknown to be detrimental to the process, therefore for convenience, thevarious steps can be performed under ambient air, although an inertatmosphere, such as nitrogen or argon, can be used if desired. Forconvenience, equimolar amounts of reactants are typically used; however,molar ratios can vary from about 1-2 equivalents, relative to the otherreactant. The pH for most steps is typically about 2 pH to about 12 pH,although, as mentioned below, the pH for Step 2 must be very acidic. Thesolvent to be used for the various steps will depend on the nature ofthe reactants and other conditions and can be, e.g., ethyl acetate,isopropyl acetate, toluene, dichloromethane dioxane, methylene chloride,toluene, acetone, methylethylketone, THF, DMF, alcohols and the like;however, the solvents for Steps 1 and 2 are listed below.

For Step 1, a typical temperature is about 10° C. to about 90° C.Preferably in Step 1, the reaction mixture is initially heated to about50° C. to about 90° C., and then cooled to crystallize the desiredcompound, e.g., at a temperature of about 10° C. to about 40° C. Theamount of resolving agent, i.e., (R)-α-methylbenzylamine, employed istypically about 0.7 molar equivalents to about 1.5 molar equivalentsrelative to formula (XI). The solvent for Step 1 is a mixture of anester or an alkyl nitrile and an alcohol. Examples of esters include,e.g., alkyl acetates, such as isopropyl acetate, t-butyl acetate, ethylacetate and the like. Examples of alkyl nitrites include, e.g.,acetonitrile and the like. Examples of alcohols include methanol,ethanol, isopropanol and the like. The ratio of ester or alkyl nitrileto alcohol can vary from about 90:10 to about 10:90, preferably about75:25 to about 25:75, and most preferably about 50:50, the precedingratios being based on volume:volume. The most preferred solvent is amixture of ethyl acetate:2-propanol (50:50, vol:vol).

For Step 2, a typical temperature is about 10° C. to about 30° C.,preferably about 20° C. to about 25° C. Due to the presence of the acid,the pH for Step 2 is acidic and is typically about a pH of 1 or less.The solvent for step 2 is a mixture of an aqueous mineral acid and anorganic solvent which forms a biphasic solvent comprising and aqueousand organic phases. The ratio (volume:volume) of aqueous mineralacid:organic solvent can vary widely, e.g., 90:10-10:90, more typically60:40-40:60. The desired compound of formula (X) can be recovered fromthe organic phase using conventional purification and/or separationtechniques known in the art such as distillation, filtration and thelike. To increase yield, multiple extractions from the aqueous phase canbe performed with the organic layers combined and then washed with anaqueous inorganic salt solution, such as a 10-40% by weight aqueoussolution of sodium chloride. Strong mineral acids are typically used forStep 2, e.g., HCl, H₂SO₄ and the like. The strength of the acid isstrong enough for forming the desired compound, typically about 1 N toabout 6 N, with about 2 N being preferred. The organic solvent can beethyl acetate, isopropyl acetate, toluene, dichloromethane dioxane,methylene chloride, toluene, acetone, methylethylketone, THF, DMF andthe like.

In U.S. Ser. No. 10/171,706, General Procedure A describes forming thecompound of formula (XIII) by treatment of the compound of formula (XIV)with LiOH and H₂O₂. Another aspect of present process eliminates theneed for using H₂O₂, thereby resulting in a process that is much safer,particularly upon scale-up.

In Step i, the alkoxide of p-methoxybenzyl alcohol can be formed in situby contacting p-methoxybenzyl alcohol with an organic base such asLiHMDS, NaHMDS, and the like. The solvent for Step i can be, forexample, diethyl ether, DMF, NMP, THF and the like. The temperature forStep i is not known to be critical and can vary from about 10° C. toabout 40° C. and, for convenience, is typically preferred at RT, e.g.,about 20° C. to about 25° C.

For Step ii, the strong organic acid can be formic acid,p-toluenesulfonic acid, and the like. The acid typically solubilizes thecompound of formula (XV), and therefore serves as the solvent for thereaction. The amount of acid is, therefore sufficient to solubilize anddeprotect the compound of formula (XV). The temperature for Step ii isnot known to be critical and can vary from about 10° C. to about 40° C.and, for convenience, is typically preferred at RT, e.g., about 20° C.to about 25° C.

For both Steps i and ii, the desired products can be purified andconcentrated using conventional techniques known in the art. Forexample, a mixture of ethyl acetate and aqueous acid or base can beadded to the reaction mixture to form a biphasic solution wherein thedesired product will be in the organic phase. After separation of theorganic phase, it can, if desired, be subject to multiple extractionswith the same or different solutions. Typical acids for this use arestrong mineral acids such as HCl, H₂SO₄, and the like, and typical basesare sodium carbonate, and the like. Removal of the solvent can beaccomplished using conventional techniques, e.g., distillation underreduced pressure. Further purification of the desired product can alsobe preformed, e.g., using chromatography such as flash chromatography,HPLC, and the like.

Compounds of formula (XIII) can be converted to active anti-bacterialcompounds of formula (IX), by contacting the compounds of formula (XIII)with a compound of formula (VI′)

in the presence of hydrogen gas and a palladium on carbon catalyst in asuitable solvent to form a compound of formula (XXVII)

Insofar as the production of starting materials is not particularlydescribed, the compounds are known or may be prepared analogously tomethods known in the art or as disclosed in the examples hereinafter. InU.S. Ser. No. 10/171,706, General Procedure A describes forming thecompound of formula XXVII.

Furthermore, another aspect of the present invention provides a novelprocess for preparing active anti-bacterial compounds of formula (IX) bytreatment the compounds of formula (VIII) with hydrogen atsub-atmospheric partial pressures in the presence of a palladiumcatalyst in ethanol. The present process minimizes production ofby-product, thereby resulting in a process that is environmentallybenign. The reaction may be carried out by sparging a gaseous mixture ofhydrogen and nitrogen at 1 atm total pressure in a reaction mixturecontaining compound of formula (VIII), ethanol and a palladium catalyst,e.g., palladium on carbon. The desired hydrogen partial pressure isattained by varying the relative flow rate of nitrogen and hydrogen. Areasonable reaction time is required, i.e., the reaction is allowed toproceed until the desired product is formed.

More specifically, another aspect of the present invention is directedto a process for preparing a compound of formula (IX)

wherein

-   -   X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF₂—,        —C═N(OR)— or —CH(F)—;    -   R₁ is aryl or heteroaryl, preferably

-   -   each of R₂, R₃, R₄ and R₅ independently is hydrogen or alkyl, or        (R₂ or R₃) collectively form a C₄-C₇cycloalkyl, preferably R₂,        R₃, R₅ are hydrogen and R₄ is n-butyl;    -   n is 0-3, preferably 1.        Comprising a step:

Converting the compound of formula (XXV)

whereinY is a hydroxy-protecting group, preferably benzyl,to the compound of formula (IX) by removing the hydroxyl-protectinggroup by contacting the compound of formula (XXV) with molecularhydrogen at hydrogen partial pressures below 1 atm, preferably about 0.1atm to about 0.24 atm, while maintaining a total pressure of about 1 atmin the presence of a palladium catalyst, such as 5% Pd/C, in a suitablesolvent, preferably ethanol, at about 10 to about 30° C., typicallyabout 20° C.

When the debenzylation with molecular hydrogen is carried out at typicalconditions (e.g., hydrogen partial pressures ≧1 atm) hydrogenolysis ofthe N—O bond in the pyridine N-oxide moiety occurs to a significantextent (i.e. yields >1%), resulting in production of a by-product(designated as “des-oxy C10”) in substantial amounts.

Because des-oxy C10 is difficult to separate from the reaction mixtureby crystallization, it is highly desirable to eliminate or at leastlimit its production to very small amounts.

A means has been found to conduct the debenzylation very selectively,i.e., with des-oxy C10 yields of under 1%, by performing the reaction athydrogen partial pressures below 1 atm. The examples 14 and 15 describethe experimental methods and results in detail.

Another aspect of the present invention is selective O-debenzylation inthe presence of pyridine N-oxides via hydrogen transfer using formicacid/4-methylmorpholine.

The penultimate step of a synthesis of the compound of formula (IX)comprises a catalytic removal of hydroxy-protecting group by contactingthe compound of formula (XXV) with hydrogen in the presence of acatalyst such as Pd/C. The compound of formula (XXV) may include apyridine N-oxide group; when the removal of hydroxy-protecting group iscarried out at typical conditions (e.g., hydrogen partial pressures ator above 1 atm) hydrogenolysis of the N—O bond in the pyridine N-oxideoccurres to a significant extent, resulting in production of by productin significant amounts. The latter is difficult to separate.

The deprotection can be carried out selectively via hydrogen transferinstead of using molecular hydrogen. A means has been found to conductdeprotection very selectively with a hydrogen transfer reagentcomprising 4-methylmorpholine and formic acid. Preferably 1.6 eq of4-methylmorpholine and 1.4 eq of formic acid in the presence of acatalyst. Such chemical transformatin occurs at elevated temperatures,preferably reaction mixture is being heated at about 45° C. for about25±10 min.

The following abbreviations are used:

HPLC=high performance liquid chromatographyAc=acetylFmoc=9-fluorenylmethyl-oxycarbonylMom=methoxy methyl etherMem=methoxy ethoxy methyl etherNPEOC=4-nitrophenethyloxycarbonylNPEOM=4-nitrophenethyloxy-methyloxycarbonyl

The following abbreviations are used:

DMAP=dimethylaminopyridineDMF=dimethylformamideEtOAc=ethyl acetateEtOH=ethanolHPLC=high performance liquid chromatographyMe=methylMeOH=methanolRT=room temperatureTHF=tetrahydrofuranNvom=nitroveratryl oxymethyl etherPh=phenyl

NMP=N-methylpryrrolidone

DABCO=1,4-diazabicyclo[2.2.2]octanepsi=pounds per square inchTBDMS=t-butyldimethylsilylTMSCl=trimethylsilyl chlorideaq.=aqueousEt=ethyliPr=isopropylBn=benzylDABCO=1,4-diazabicyclo[2.2.2]octane

The following examples are to illustrate the invention but should not beinterpreted as a limitation thereon.

EXAMPLE 1 3-Hydroxy-2-methylenehexanoic Acid Methyl Ester

A mixture of butanol (72.11 g, 1.000 mmol), methyl acrylate (129.14 g,1.500 mmol) and DABCO (22.44 g, 200 mmol) is allowed to react at roomtemperature under N₂ for 7 days. The reaction mixture is concentrated onRotavap under reduced pressure (20 mbar) until no further solventdistills. The residue colorless liquid is dissolved in toluene (800 mL)and washed sequentially with 2 N HCl acid (250 mL), water (250 mL),saturated aq. sodium bicarbonate solution (120 mL) and water (150 mL).The toluene layer is concentrated on Rotavap under reduced pressure (20mbar) until no further solvent distills to afford3-hydroxy-2-methylenehexanoic acid methyl ester (96.7 g, yield: 61.1%)as a colorless liquid.

EXAMPLE 2 3-Acetoxy-2-methylenehexanoic Acid Methyl Ester

A mixture of 3-hydroxy-2-methylenehexanoic acid methyl ester (55.37 g,350 mmol) and DMAP (4.28 g, 35 mmol) in toluene (400 mL) is cooled to0-5° C. and to it is added acetic anhydride (42.88 g, 420 mmol) dropwisein ˜30 minutes while maintaining the temperature at 0-5° C. Theresulting solution is allowed to warm to room temperature in 1 hour.After stirring for 3 hours at RT, the reaction mixture is cooled to 0-5°C. and to it is added 1 N HCl acid (80 mL), in 20 minutes. The organiclayer is separated and washed sequentially with water (80 ml), saturatedaqueous sodium bicarbonate solution (2×80 mL) and water (80 mL). Theorganic layer is concentrated on Rotavap under reduced pressure (20mbar) until no further solvent distills to afford3-acetoxy-2-methylenehexanoic acid methyl ester (68.3 g, yield: 97.5%)as a colorless liquid.

EXAMPLE 3 2-[[(Phenylmethoxy)amino]methyl]-2-hexenoic Acid Methyl Ester

A mixture of 3-acetoxy-2-methylenehexanoic acid methyl ester (4.00 g, 20mmol) and O-benzylhydroxylamine (7.39 g, 60 mmol) in THF (30 mL) isallowed to react at RT under N₂ for 2 days. The reaction mixture isconcentrated on Rotavap under reduced pressure (20 mbar) until nofurther solvent distills. The residue liquid is dissolved in ethylacetate (75 mL) and washed with saturated aqueous sodium bicarbonatesolution (50 mL). The ethyl acetate layer is concentrated on Rotavapunder reduced pressure (20 mbar) until no further solvent distills toafford a colorless liquid (11.2 g).

The crude material is chromatographed (silica gel, 5% ethyl acetate inheptane) to afford a ˜1:1 mixture of (E) and(Z)-2-[[(phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester (4.01g, yield: 76%) as a colorless liquid.

EXAMPLE 4 2-[[(Phenylmethoxy)amino]methyl]-(2S)-hexanoic Acid MethylEster

A ˜1:1 mixture of (E) and(Z)-2-[[(phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester (3.95g, 15 mmol), bis(norbornadiene)rhodium(I) tetrafluoroborate (56.1 mg,0.15 mmol) and (1S,1′S,2R,2′R)-TangPhos (47.3 mg, 0.165 mmol) inde-oxygenated methanol (90 mL) in a Parr bottle is hydrogenated under H₂(45-55 psi) at RT for 24 hours. The reaction mixture is concentrated onRotavap under reduced pressure (20 mbar) until no further solventdistills. The residue liquid is dissolved in a mixture of ethylacetate/heptane (50/50, 10 mL) and filtered through a silica gel pad(˜12 g). The silica gel pad is rinsed with a mixture of ethylacetate/heptane (50/50, 200 mL). The filtrates are combined andconcentrated on Rotavap under reduced pressure (20 mbar) until nofurther solvent distills to afford2-[[(phenylmethoxy)amino]methyl]-(2S)-hexanoic acid methyl ester (3.76g, yield: 94%, S:R=98.0:2.0) as a liquid.

2-[[(Phenylmethoxy)amino]methyl]-(2S)-hexanoic acid methyl is alsoprepared using (2R,5R)-Me-Duphos (yield: 95%, R:S=98:2).

EXAMPLE 5 2-[[(Phenylmethoxy)amino]methyl]-(2R)-hexanoic Acid MethylEster

(1R,1′R,2S,2′S)-TangPhos affords2-[[(phenylmethoxy)amino]methyl]-(2R)-hexanoic acid methyl ester (yield:96%, R:S=98.6:1.4)

Similarly, (2S,5S)-Me-Duphos affords2-[[(phenylmethoxy)amino]methyl]-(2R)-hexanoic acid methyl ester (yield:98%, R:S=98.8:1.2).

EXAMPLE 6 1-Benzyloxy-(3S)-butyl-2-azitidinone

To a solution of 2-[[(phenylmethoxy)amino]methyl-(2S)-hexanoic acidmethyl ester (265 mg, 1.0 mmol) in tetrahydrofuran (5.0 ml) at 0° C. isadded dropwise, 3.0 M methylmagnesium chloride (0.76 mL, 2.30 mmol) at arate maintaining the same internal temperature. The resulting solutionis stirred for 1 hour at 0-3° C. and the reaction is quenched byaddition of pH 7 phosphate buffer (5.0 ml). Ethyl acetate (30 mL) isadded, the organic layer is separated and washed with water (20 mL). Theorganic layer is concentrated under reduced pressure to afford the crudeproduct as an oil which is purified by flash chromatography on silicagel to give 1-benzyloxy-(3S)-butyl-2-azitidinone (112 mg, 50% yield,S:R=92.7:7.3)).

EXAMPLE 7 1-Benzyloxy-(3R)-butyl-2-azitidinone

2-[[(phenylmethoxy)amino]methyl-(2R)-hexanoic acid methyl ester affords1-benzyloxy-(3R)-butyl-2-azitidinone.

The examples 8, 9, 10 and 11 that follow make reference to reactionscheme 1 below:

EXAMPLE 8 Preparation of (±)-2-butyl-3-hydroxypropionic Acid (4)

A 12 L, 4-necked, round-bottomed flask, equipped with a mechanicalstirrer, digital thermometer, and nitrogen inlet-outlet is charged with2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) andisopropanol (4.5 L). The solution is cooled to an internal temperatureat 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol)in tetrahydrofuran is added over a period of 1.5 hours while maintainingthe internal temperature at 15-25° C. The stirring is continued for anadditional 3 h. The reaction mixture is cooled to an internaltemperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L)over a period of 1 hour while maintaining the internal temperature at10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) tocollect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). Thissuspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) andthe biphasic mixture is stirred for 1 hour. The organic layer isseparated and the aqueous layer is extracted with ethyl acetate (2.0 L).The combined organic layers are washed with 20% aqueous solution ofsodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until nofurther solvent distills to afford crude (±)-2-butyl-3-hydroxypropionicacid (4, 349.4 g, 100%) as a colorless liquid, which is used as such inthe next step.

EXAMPLE 9 Resolution of (±)-2-butyl-3-hydroxypropionic Acid (4)

A 5 L, 4-necked, round-bottomed flask, equipped with a mechanicalstirrer, digital thermometer, reflux condenser, addition funnel withnitrogen inlet-outlet, and heating mantle is charged with(R)-α-methylbenzylamine (280.7 g, 2.316 mol), isopropanol (1.9 L) andethyl acetate (1.63 L). The solution is stirred and heated to aninternal temperature at 60-65° C., and a solution of(±)-2-butyl-3-hydroxypropionic acid (4, 322.5 g, 2.206 mol) in ethylacetate (0.2 L) is added over a period of 15 min while maintaining theinternal temperature at 60-70° C. The addition funnel is washed withethyl acetate (0.2 L) and added to the mixture. The solution is cooledto 20-25° C. over a period of 2 hours and the resulting suspension isstirred at the same temperature for an additional 5 hours. The solidsare collected by filtration, washed with a mixture of ethylacetate-isopropanol (2:1 ^(v)/_(v)) in two equal portions of 0.5 L each,and dried at 50-53° C. (13-49 mbar) to afford crude(R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5,246.3 g; 41.7%); (R):(S)=94.1:5.9.

Crude (R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammoniumsalt (5, 246.3 g) is transferred to a 5 L, 4-necked, round-bottomedflask, equipped with a mechanical stirrer, digital thermometer, refluxcondenser, addition funnel with nitrogen inlet-outlet and heatingmantle. Ethyl acetate (1.225 L) and isopropanol (1.225 L) are thenadded. The suspension is stirred and heated to an internal temperatureat 70-80° C. over a period of 1 hour to obtain a solution. The solutionis cooled to 20-25° C. over a period of 2 hours and the resultingsuspension is stirred at the same temperature for an additional 5 hours.The solids are collected by filtration, washed with a mixture of ethylacetate-isopropanol (2:1 ^(v)/_(v)) in two equal portions of 0.4 L each,and dried at 50-53° C. (13-49 mbar) to afford pure(R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5,215.6 g; 36.5%; 73.0% of theory); m.p. 145-147° C.; [α]_(D) +8.8 (c=1.0,CH₃OH); (R):(S)=99.3:0.7.

EXAMPLE 10 (R)-2-Butyl-3-hydroxypropionic Acid (1)

(R)-2-Butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5,10.0 g) is dissolved in 2 N HCl (40.0 mL) and isopropyl acetate (50.0mL) is added to the mixture. After mixing for 5 min, the organic layeris separated and the aqueous layer is extracted with isopropyl acetate(3×50.0 mL). The combined organic layers are washed with water (20.0 mL)and concentrated under vacuum (20 mbar) until no further solventdistills to afford (R)-2-butyl-3-hydroxypropionic acid (1, 5.4 g, 98%);oil; [α]_(D) +6.5 (c=1.0, CH₃OH), (R):(S)=99.3:0.7.

EXAMPLE 11 (S)-2-Butyl-3-hydroxypropionic Acid

(S)-2-Butyl-3-hydroxypropionic acid is prepared by the resolution of(±)-2-butyl-3-hydroxypropionic acid (4) with (S)-α-methylbenzylamine ina similar manner as described above for the (R)-enantiomer.(S)-2-butyl-3-hydroxypropionic acid (S)-α-methylbenzylammonium salt,yield 33.2% (66.4% of theory); m.p. 145-147° C.; [α]_(D) −8.9 (c=1.0,CH₃OH); (S)-2-butyl-3-hydroxypropionic acid: yield 98%; oil; [α]_(D)−6.6 (c=1.0, CH₃OH); (R):(S)=0.4:99.6.

TABLE 1 Resolution of 4 (1.0 g) with (R)-α-methylbenzylamine (1.0 equiv)Solvent Enantiopurity of volume (mL/g 5 Isolated Entry Solvent (ratio)of 4) (R):(S) Yield (%) 1 CH₃CN:CH₃OH 13.6 85.6:14.4 31.0 (75:25) 2EtOAc:CH₃OH 10.0 96.0:4.0 26.7 (70:30) 3 EtOAc:acetone 10.0 54.7:45.373.3 (70:30) 4 EtOAc:C₂H₅OH 10.0 89.3:10.7 36.4 (70:30) 5 EtOAc:i-PrOH12.0 94.1:5.9 41.7 (50:50) Recrystallization 10.0 99.3:0.7 36.5

EXAMPLE 12 Displacement of Chiral Auxiliary with 4-methoxybenzyl Alcohol

To XIV (5.1 g, 11.6 mmol in THF (30 ml)) is added a mixture of4-methoxybenzyl alcohol (1.93 g, 13.9 mmol), LiHMDS (1.95 g, 11.6 mmol)and tetrahydrofuran (40 mL) at 20° C. slowly and dropwise. The resultingmixture is stirred for 2 hours at 22° C. Ethyl acetate (150 mL) and 1 NHCl solution (40 mL) are added to the reaction mixture and the organiclayer is separated. The organic layer is washed with water (50 mL),saturated NaHCO₃ solution (50 mL) and water (50 mL). The solvent isremoved under reduced pressure to afford a crude product as an oil whichis purified by flash chromatography on silica gel to give the desired XV(4-methoxybenzyl ester, 2.81 g, 60% yield).

EXAMPLE 13 Deprotection of 4-methoxybenzyl Ester to (XIII)

A mixture of 4-methoxybenzyl ester, XV, (820 mg, 2.05 mmol) and formicacid (8 mL) is stirred at 22° C. for 2 hours. The reaction mixture isconcentrated under reduced pressure. Ethyl acetate (50 mL) and 1 NNa₂CO₃ solution (15 mL) are added to the resulting residue and theaqueous layer is separated. The aqueous layer is acidified with 2 N HClsolution (10 mL) and extracted with ethyl acetate (2×30 mL). The organiclayer is washed with water (20 mL). The solvent is removed under reducedpressure to afford a crude product as an oil which is purified by flashchromatography on silica gel to give the XIII (420 mg, 74% yield).

The examples 14 and 15 that follow make reference to reaction schemebelow:

EXAMPLE 14 Debenzylation at Hydrogen Pressure of 0.24 atm

A means to operate at subatmospheric H₂ partial pressures whilemaintaining a total pressure of 1 atmospheric was achieved (thusobviating solvent evaporation and leaks) by performing the reactionusing H₂ diluted with N₂). The apparatus comprises two calibrated massflow controllers, one for N₂ and the other for H₂, which allow for acontrolled flow rate of each gas based on an inputted set point. Byvarying the relative flow rates of the two gases, any H₂ partialpressure can be achieved. A 250-mL jacketed vessel equipped with agassing agitator is charged with 8 g of C9, 62 g (˜80 mL) of 200-proofethanol, and 1.3 g of 5% Pd/C catalyst (Degussa, E1070 NO 5% Pd, watercontent 66.2 of wt %, Lot # 6JLG30), or 0.44 g of catalyst on a drybasis. The headspace is purged of air by flowing N₂ through both massflow controllers at about 30 cm³/min. The reactor is kept open to theatmospheric, giving a pressure of 1 atm in the vessel. The reaction isstarted by setting flow rates of 28 and 9 cm³/min, respectively, on theN₂ and H₂ mass flow controllers, giving a H₂ partial pressure of 0.24atm. A 700 rpm agitation rate is used, and the reaction temperature is20° C. The lower hydrogen concentration in the liquid-phase gives aslower reaction, with the time required for 100% C9 conversion beingabout 3 h vs. 1.7 h for the 1-atm H₂ partial pressure case. Asignificant des-oxy C10 selectivity advantage is observed at 0.24H₂partial pressure. For example, a 0.99% des-oxy C10 yield is obtained at97.6% C9 conversion, giving a selectivity of 1.01% vs. a des-oxy C10yield of 6.07% at 99.8% C9 conversion, giving a selectivity of 6.1%, inthe 1-atm case.

EXAMPLE 15 Debenzylation at a Hydrogen Partial Pressures of 0.1 atm

A 250-mL jacketed vessel equipped with a gassing agitator is chargedwith 8 g of C9, 62 g (˜80 mL) of 200-proof ethanol, and 1.4 g of 5% Pd/Ccatalyst (Degussa, E1070 NO 5% Pd, water content 68.05 of wt %, Lot #CC1-2215), or 0.45 g of catalyst on a dry basis. The headspace is purgedof air by flowing N₂ through both mass flow controllers at about 30cm³/min. The reactor is kept open to the atmospheric, giving a pressureof 1 atm in the vessel. The reaction is started by setting flow rates of28 and 3 cm³/min, respectively, on the N₂ and H₂ mass flow controllers,giving a H₂ partial pressure of 0.1 atm. A slower reaction is obtainedrelative to the 0.24H₂ partial pressure case (4.5 vs. 3 h), but thereaction is not unreasonably long for a production process. Even morefavorable des-oxy C10 selectivities are obtained at 0.1 atm H₂ partialpressure, viz., 0.78% des-oxy C10 yield at 99.8% C9 conversion, giving ades-oxy C10 selectivity of 0.78% vs. a 0.99% des-oxy C10 yield at 97.6%C9 conversion, giving a selectivity of 1.01%, for the 0.24-atm H₂partial pressure case.

Example 16 makes reference to reaction scheme below:

EXAMPLE 16

A jacketed vessel is charged with 169.85 mmol solution of C9 in ethanol,27.497 g of 4-methylmorpholine and 138.0 g of 200-proof ethanol. Afterstirring reaction mixture at about 22° C. 10.845 g of formic acid isadded at a rate to maintain 22° C. following by addition of 69.0 g of200-proof ethanol. 8.016 g of 10% Pd/C are added to the reactionfollowing by addition of 44.28 g of 200-proof ethanol. Mixture is heatedto about 45° C. for a period 25±10 min. Batch is held at thistemperature for 2-3 hours. Filtered and twice washed with ethanolyielding C10.

1. A process comprising contacting the compound of formula (III)

with hydrogen in the presence of a chiral ligand and a catalytic amountof a hydrogenation catalyst in a suitable solvent and under conditionssuitable to form a compound of the formula (IV)

wherein R is alkyl; each of R₂, R₃, and R₁₀ independently is hydrogen oralkyl, or (R₂ or R₃) collectively form a C₄-C₇cycloalkyl and Y is ahydroxyl protecting group.
 2. The process of claim 1 wherein the chiralligand is (2S,5S)-Me-Duphos, or (1R,1′R,2S,2′S)-TangPhos and thehydrogenation catalyst is a metal catalyst containing rhodium (Rh I) orruthenium (Ru II).
 3. The process of claim 2 wherein the temperature isabout 10° C. to about 50° C., the solvent is dioxane, methylenechloride, dichloromethane, toluene, acetone, methylethylketone, THF,isopropyl acetate, DMF, or an alcohol, the hydrogen is in the form ofhydrogen gas, the pressure is about 40 psi to about 100 psi, the amountof chiral ligand is about 1 mole % to about 15 mole % relative to thesubstrate, the hydrogenation catalyst is bis(norbornadiene)rhodium(I)tetrafluoroborate, and the amount of catalyst is about 1 mole % to about5 mole % relative to the substrate.
 4. The process of claim 1 wherein Ris methyl; R₁₀ is n-propyl, and each of R₂, and R₃, is hydrogen.
 5. Aprocess comprising contacting a compound of the formula (III)

with hydrogen in the presence of (2R,5R)-Me-Duphos or(1S,1′S,2R,2′R)-TangPhos and a catalytic amount of a hydrogenationcatalyst in a suitable solvent and under conditions suitable to form acompound of the formula (IV′)

wherein R is alkyl; R₁₀ is hydrogen or alkyl and Y is a hydroxylprotecting group. 6-35. (canceled)
 36. The process of claim 1 whereinthe compound of the formula (III) is2-[[(Phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester.
 37. Theprocess of claim 1 wherein the compound of the formula (IV) is2-[[(Phenylmethoxy)amino]methyl]-(2R)-hexanoic acid methyl ester. 38.The process of claim 5 wherein R is methyl and R₁₀ is n-propyl.
 39. Theprocess of claim 5 wherein the compound of the formula (III) is2-[[(Phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester.
 40. Theprocess of claim 5 wherein the compound of the formula (IV′) is2-[[(Phenylmethoxy)amino]methyl]-(2S)-hexanoic acid methyl ester.